The eye, particularly the conjunctiva, has a relatively large number of mast cells. When allergens are present, they can bind to immunoglobulins on the surface of these mast cells and trigger the breakdown, or what is known as the degranulation, of the cell. Upon degranulation, mast cell components, including histamine, are released into the environment outside the mast cell. Through a variety of mechanisms, these components can be responsible for symptoms associated with allergic responses such as itching, redness, lid swelling, vasodilatation and chemosis.
Various therapies have been pursued in order to treat the symptoms of allergies. For example, such therapy has included the use of anti-allergics and anti-histamines.
Anti-allergics are compounds which prevent, inhibit or alleviate allergic reactions. Disodium cromoglycate (DSCG) has been used as an anti-allergic to treat allergic conditions such as: vernal, allergic or chronic conjunctivitis (Leino et al., Clinical Trial Of The Topical Use Of Disodium Cromoglycate In Vernal, Allergic And Chronic Conjunctivitis, Acta Ophthalmologica, volume 58, pages 121-124, 1980); vernal keratoconjunctivitis (M. El Hennawi, A comparison between 2% and 4% sodium cromoglycate eye drops in the treatment of vernal keratoconjunctivitis, Current Eye Research, volume 2, No. 11, pages 765-768, 1982/1983); and giant papillary conjunctivitis (Meisler et al., Cromolyn Treatment of Giant Papillary Conjunctivitis, Archives in Ophthalmology, volume 100, pages 1608-1610, 1982). DSCG has been reported to be irritating to some patients (H. Bruce Ostler, Acute Chemotic Reaction to Cromolyni, Archives in Ophthalmology, volume 100, No. 1, pages 412-413, 1982). Cyano phenylene dioxamic compounds disclosed generally in U.S. Pat. No. 3,993,679 issued to Hall et al., are also anti-allergic compounds which have been used in preventing allergic reactions resulting in mast cell degranulation. Although these compounds can be anti-allergic, they can also cause eye irritation and systemic side effects; see for example, Watt et al., Protective effect of lodoxamide tromethamine on allergen inhalation challenge, Journal of Allergy and Clinical Immunology, volume 66, No. 4, pages 286-294 (1980).
Anti-histamines are compounds which are administered to antagonize the action of histamine, released from mast cells in response to the presence of allergens. As histamine antagonists, they reduce the redness, itching and swelling caused by the action of histamine on the target tissues in the conjunctiva. They serve to prevent or alleviate many of the symptoms which can result from degranulation of mast cells. However, anti-histamines have also been associated with adverse reactions such as diminished alertness, slowed reaction times and somnolence (Goodman and Gillman's the Pharmacological Basis of Therapeutics, Eighth Edition, Pergamon Press, New York, pages 575-588 (1990)).
In order to ascertain compounds with specific mast cell stabilizing efficacy, studies have been conducted with various mast cell lines. However, mast cells differ between species. For example, it is now well established that the types of mast cells which exist in rodents are different from those in humans. See, for example, THE LUNG: Scientific Foundations, Raven Press, Ltd., New York, Ch. 3.4.11 (1991). Moreover, mast cell populations of various tissues within the same species differ in phenotype, biochemical properties, functional and pharmacological responses and ontogeny. These recognized differences in mast cells, both between and within species, are referred to as mast cell heterogeneity. See, for example, Irani et al., Mast Cell Heterogeneity, Clinical and Experimental Allergy, volume 19, pages 143-155 (1989). Because different mast cells exhibit different responses to pharmacological agents, it is not obvious that compounds claimed to be anti-allergic ("mast cell stabilizers") will have clinical utility in specific mast cell populations. The assumption that mast cells are a homogeneous population, and that experiments in rat mast cells would be predictive of those in human cells, is also known to be incorrect (Church, Is Inhibition of Mast Cell Mediator Release Relevant to the Clinical Activity of Anti-Allergic Drugs?, Agents and Actions, volume 18, 3/4, pages 288-293, (1986)).
Examples exist in the art in which mast cell stabilizing drugs inhibit only select populations of mast cells. Disodium cromoglycate is an anti-allergic drug whose local effects are believed to be due to inhibition of mast cell degranulation (Church, Agents and Actions, at 288). This drug was shown to inhibit rodent mast cell degranulation. In human trials, 100 .mu.M of the drug inhibited mast cells obtained from bronchoalveolar lavage fluid. In dispersed human lung mast cell preparations, 1000 .mu.M of the drug was required to inhibit only 25% to 33% of histamine release. Finally, histamine release from human skin mast cells was not inhibited at all by disodium cromoglycate. Pearce et al., Effect of Disodium Cromoglycate on Antigen Evoked Histamine Release from Human Skin, Clinical Experimental Immunology, volume 17, pages 437-440 (1974); and Clegg et al., Histamine Secretion from Human Skin Slices Induced by Anti-IgE and Artificial Secretagogues and the Effects of Sodium Cromoglycate and Salbutamol, Clinical Allergy, volume 15, pages 321-328 (1985). These data clearly indicate that one can not predict with certainty that drugs which possess inhibitory effects on one mast cell population will affect all mast cell populations.
One disadvantage to the ophthalmic use of reported anti-allergic drugs which in fact have no stabilizing effect on human conjunctival mast cells is an increased dosage frequency. Because the effectiveness of ophthalmic formulations containing drugs which do not have conjunctival mast cell activity stems primarily from a simple irrigation effect, more frequent doses are typically required than for drugs which do inhibit conjunctival mast cell degranulation. Therefore, topical ophthalmic formulations which contain drugs having conjunctival mast cell activity may only need to be applied once every 12-24 hours instead of once every 2-4 hours.
Dihydropyridines, such as nicardipine and nifedipine have been disclosed in the art to inhibit histamine release from rat mast cells (Tanazaki et al., Inhibitory Effect of Nifedipine and Cromolyn Sodium on Skin Reactions and .sup.45 Ca Uptake and Histamine Release in Rat Mast Cells Induced by Various Stimulatory Agents, International Archives of Allergy and Applied Immunology, volume 72, pages 102-109 (1983)), and to inhibit histamine release from human lung and tonsillar cells (Kim et al., Inhibition of Histamine Release from Dispersed Human Lung and Tonsillar Mast Cells by Nicardipine and Nifedipine, British Journal of Clinical Pharmacology, volume 19, pages 631-638 (1985)). Nowhere in the art, however, has it been disclosed to use these types of drugs to stabilize human conjunctival mast cells.
What is needed are drug compounds to prevent the release of mediators of allergic response from the mast cells of the human conjunctiva, the target cells for treating allergic eye diseases. What is also needed are local administration methods for the treatment of allergic eye disease. Furthermore, what is needed are prophylactic therapies in contrast with symptom treating approaches.